Maternal pre-pregnancy obesity is associated with altered placental transcriptome
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ABSTRACT: Maternal obesity is becoming a major health consideration for successful pregnancy outcomes. There is growing proof that maternal obesity has a negative influence on placental development and function, thereby adversely influencing offspring programming and health outcomes. However, the molecular mechanisms underlying these processes are so far poorly understood. We set out to analyse term placenta whole transcriptome in obese (n=5) and normoweight women (n=5), using Affymetrix microarray platform compromising of 50,000 probe sets. Our analysis shows that the placental transcriptome differs between normoweight and obese women. Different processes and pathways among placenta from obese women were dysregulated, including inflammation and immune responses, lipid metabolism, cell death and survival and cancer pathways, vasculogenesis and angiogenesis, and glucocorticoid receptor signaling pathway. Together, this global gene expression profiling approach demonstrates and confirms that maternal obesity creates a unique in utero environment that impairs placental transcriptome.
Project description:Maternal obesity in pregnancy is associated with increased birth-weight, obesity and premature mortality in adult offspring. The Effect of Metformin on Maternal and Fetal Outcomes in Pregnant Obese Women (EMPOWaR) trial was a randomised, double-blind, placebo-controlled trial carried out to determine whether exposure to Metformin would affect the offspring birth-weight centile. Obese women exposed to Metformin had increased insulin sensitivity at 36 weeks of pregnancy, but there were no differences in offspring birthweight. We obtained the placentas from these women to determine whether there were differences in expression of genes regulating fetal growth and metabolism. In a complementary study we investigated DNA methylation in the same samples.
Project description:Maternal obesity in pregnancy is associated with increased birth-weight, obesity and premature mortality in adult offspring. The Effect of Metformin on Maternal and Fetal Outcomes in Pregnant Obese Women (EMPOWaR) trial was a randomised, double-blind, placebo-controlled trial carried out to determine whether exposure to Metformin would affect the offspring birth-weight centile. Obese women exposed to Metformin had increased insulin sensitivity at 36 weeks of pregnancy, but there were no differences in offspring birthweight. We obtained the placentas from these women to determine whether there were differences in DNA methylation of genes regulating fetal growth and metabolism. In a related study we investigated the gene expression in the same samples.
Project description:Maternal obesity has both a direct effect on the outcome of pregnancy but also programs the fetus for obesity and metabolic syndrome in later life. Due to its roles at the interface between mother and fetus, the placenta transduces and mediates the effects of the obese intrauterine environment on the fetus. Here we have generated genome-scale high-resolution maps of 5mC and 5hmC in human placentas of obese and healthy weight pregnancies. Widespread alterations to the placental epigenome identified across the genome in the setting of maternal adiposity are primarily characterized by increase in 5mC and reciprocal decrease in 5hmC. This is also evident at the two pregnancy-associated gene clusters on chromosomes 17 and 19. In addition, maternal adiposity is associated with downregulation of ten-eleven translocation (TET) and isocitrate dehydrogenase (IDH) family genes and is accompanied by decreased levels of α-ketoglutarate (αKG) in the placenta. Of note, αKG levels exhibit a close positive correlation with both ascorbate and aconitate levels and less substantial but significant association with global 5hmC levels and placenta-specific gene expression. These observations suggest a mechanistic linkage between obesogenic environment and conversion efficiency of 5mC to 5hmC and highlight the idea that TET-mediated active DNA demethylation pathway can sense and respond to metabolic derangements and plays a role in subsequent cellular adaptation. Collectively, this study demonstrates that altered DNA demethylation process is likely one of the mechanisms underlying metabolic modulation of the placental epigenome with maternal adiposity. Comparison of lean vs obese epigenomes in human pregnancies
Project description:Overnutrition during pregnancy inM-oM-,M-^Buences the future health of the offspring, with outcomes differing depending on the childM-bM-^@M-^Ys sex. The placenta is involved in the programming of obesity, type 2 diabetes and cardiovascular disease. Sex-specific adaptation of the placenta may be central to the differences in fetal growth and survival. The impact of diet and fetal sex on placental gene expression and epigenetic marks was investigated in mice fed a high-fat (HFD) or a control diet (CD), during the first 15 days of gestation Microarrays analysis revealed that expression was affected by maternal diet and was sexually dimorphic. We analyzed the placentae of 4 mice litters fed with an high-fat diet (HFD) and 4 with a control diet (CD). For each litter, the placenta transcriptome was analysed according to the foetus sex using the Affymetrix Human Exon 1.0 ST platform. Array data was processed by Affymetrix Exon Array Computational Tool. No technical replicates were performed.
Project description:This study assesses fatty acid composition of lipids in matched maternal plasma and placental tissue from lean, obese and gestational diabetes (GDM) women stratified by fetal sex. Obesity and GDM are associated with adverse pregnancy outcomes and program the offspring for cardiometabolic disease in a sexually dimorphic manner. We collected maternal plasma and placental villous tissue following elective cesarean section at term from women who were lean (pre-pregnancy BMI 18.5-24.9), Obese (BMI>30) and type A2 GDM (matched to obese BMI) with either a male or female fetus (n=4 each group). Lipids were extracted and fatty acid composition of different lipid classes were analyzed by LC-MS/MS to find significant changes in GDM vs Obese, GDM vs Lean, and Obese vs Lean.
Project description:Maternal obesity in mice negatively affects placental functionand maternal and fetal liver function. We performed a global proteomic analysis using a liquid-chromatography/mass-spectrometry system to investigate total and phosphorylated proteins in the placenta and fetal liver in a mouse model that combines maternal obesity with maternal androgen excess to identify changes in molecular pathways that might promote diseases in adulthood.
Project description:Pregnant women appear to be at increased risk for severe outcomes associated with COVID-19, but the pathophysiology underlying this increased morbidity and its potential impact on the developing fetus is not well understood. In this study of pregnant women with and without COVID-19, we assessed viral and immune dynamics at the placenta during maternal SARS-CoV-2 infection. Amongst uninfected women, ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term. Term placentas from women infected with SARS-CoV-2, however, displayed a significant increase in ACE2 levels. Using immortalized cell lines and primary isolated placental cells, we determined the vulnerability of various placental cell types to direct infection by SARS-CoV-2 in vitro. Yet, despite the susceptibility of placental cells to SARS-CoV-2 infection, viral RNA was detected in the placentas of only a subset (∼13%) of women in this cohort. Through single cell transcriptomic analyses, we found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited markers associated with pregnancy complications, such as preeclampsia, and robust immune responses, including increased activation of placental NK and T cells and increased expression of interferon-related genes. Overall, this study suggests that SARS-CoV-2 is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion. While this likely represents a protective mechanism shielding the placenta from infection, inflammatory changes in the placenta may also contribute to poor pregnancy outcomes and thus warrant further investigation.
Project description:To explore the interactions between the range of maternal and fetal placental cell types present, we profiled the transcriptomes of more than 50,000 single cells from matched first trimester samples of maternal blood and decidua, as well as fetal cells from the placenta itself. Demuxlet was used to discern between cells of fetal and maternal origin, from SNPs inferred from genotyping.
Project description:Overnutrition during pregnancy influences the future health of the offspring, with outcomes differing depending on the child’s sex. The placenta is involved in the programming of obesity, type 2 diabetes and cardiovascular disease. Sex-specific adaptation of the placenta may be central to the differences in fetal growth and survival. The impact of diet and fetal sex on placental gene expression and epigenetic marks was investigated in mice fed a high-fat (HFD) or a control diet (CD), during the first 15 days of gestation Microarrays analysis revealed that expression was affected by maternal diet and was sexually dimorphic.
Project description:To explore the interactions between the range of maternal and fetal placental cell types present, we profiled the transcriptomes of more than 50,000 single cells from matched first trimester samples of maternal blood and decidua, as well as fetal cells from the placenta itself. RNA-seq was done using the standard 10x chromium v2 chemistry.